New process for the preparation of alpha-amino-epsiled-caprolactam and novel intermediated formed thereby



O 1953 c. M. BRENNER EIAL 3,107,239

mmnoa menu NE] PROCESS FOR THE OF d-AIINO-i-CAPR AND NOVEL INTERMEDIATE FORIIHJ 11m! Filed D60. 28. 1960 2 shfltfl-slflfl 1 Fig. I

m5: Cir "0-! Banana an Mucus A. Stevens by wMJ- d ATTUWEYS Oct. 15, 1963 C. M. BRENNER E'I'AL PROCBS FOR THE PREPARATION 0? AND NOVE- Ira-mums Filed D00- 28. 1960 Fig. 3

oaassssass United States Patent Oflicc 3,107,239 Patented Oct. 15, 1963 3,107,239 NEW PROCESS FOR THE PREPARATION OF AMIlNO-e-CAPROLACIAM AND NOVEL INTER- A.-G., Bsel, Switzerland alums pnorlty t n w it iemnd ifi so 1959 a claim. (Cl. 260-2393) Natural lysine is one of the essential amino acids for man and the majority of domestic animals. This amino acid which is necessary to build up tissue protein must be provided by focdstutis. Compared with the other es sential amino acids present in wheat protein and to a less extent also in other cereal proteins, lysine is present in an amount which is less than that necessary for the building up of human and animal tissue. It is therefore of importance to find economic proceses for the obtention of lysine in order to be able to add this important amino acid to wheat protein or to the foodstutfs produced irom wheat, and to better adapt their amino acid content to that of the tissue protein without a noticeable increase in price.

The present invention relates to a novel process for the preparation of c-aminoe-caprolactam and its salts from a -diCillOlO-e-CQPI'OIAQBIII and to new intermediates which are formed during this process. The m-amino-e-caprolactam obtained by this process is a valuable and cheap startiug material for the synthesis of lysine. The ,-dichloror-caprolactamcaneasilybeproducedintheknownmam ner from e-caprolactam, a marketed product, and phosphorus pentachloride (I. von Braun and A. Heymonr Bmichte, 63, 502). The aaamino-e-caprolactam can easily be converted by known methods into lysine. Thus, the aim of the present invention is to convert mt-dichloroe caprolaetum in a new and simple manner into a-amino-ecaprolactam by way of new intermediates. The process according to the invention for the production of a-aminoe-caprolactam or its salts is charaauiscd by reacting amdichloro-ecaprolactam at a raised temperature, advantageouslyin alcoholicsolutionorinthemelt, withtwoto fivetimesthemolaramountofanallralimetal alcoholate, inparficularwithonepreparedfinmalkanohcycloalkanols, arylalkanols or alkenols. On completion of the reaction, the Z-mbstimted 6-aminohexene(2)-acid lactam so formed of the gmaal Formula I i cg c-B (EH: 0

Hicwhereinkrepresentstheorganieradicalofthealkali metal alcoholate reacted, in particular an alkyl, cycloalkyl, aralkyl or alkenyl radical,

isreactedwithabonthalfthemolaramountoiamineral acidsaltoihydranne. thereactionbeingperforrnedata pH of 0.8 and 3.0 and at a temperature of 60-120 0, and finallly, the hydran'ne derivative so formed is completelyhydrogenatedcatalytically.

ThenseofanalcohohforexampleofanalkanoLas solventinthefirststepoftheprocesisofadvantageas thiscansesthereactantstobebronghtinanhomogeneom Itisadvanta geousiftln'sreactionisperformedwhileexcludingwater. Asthereactionisexothermhitisonlynecessarytoapply heatatthebeginningandtowardstheendofthereaction inordertostartandthentocompleteit. Generallya fiseintemperaturenptotheboilingpointofthealcohol usedissufiicientforthispnrpoaonifthereactionisperformedinthemelhuptothemeltingpointofthemedichloro-e-caprolactam. The first step of the process according to the invention is performed with at least 2, preferably however, with 3 mols of alcoholate, e.g., sodium ethylate, per mol of ,e-dichloro--caprolactam. The alccholate corresponding to -()k in the intermediate product of the general Formula I can be that of any alkali metal desired with an aliphatic, cycloaliphatic or araliphatic alcohol; however, the alcoholatcs of low molecular alkanoh: or alkenols are preferred as they lead to products whichcanmoreeasilybedistilled. lfan alcohol is used as solvent, then advantageously the alcohol corresponding to the alkali metal alcoholate is used, e.g., sodium methylate in methanol as solvent.

In the reaction of Z-snbstitutcd 6-aminohexene(2)-acid lactam (I) with hydrazine salts, a new hydrazine tkrivative of formula C I-I Np, is obtained, which hydran'ne derivative is converted by hydrogenation intothe e-aminoecaprolactam. The reaction with a hydrazine salt of a mineral acid is performed advantageously by heating, in solution at a pH of about I, Z-substitnted 6-aminohexene (2)-acid lactam of Formula I with a sulphate, nitrate or chloride of the hydrazine. The pH of about 1 can be maintained during the reaction either by bufiering or by manual or automatic titration of the solution. 'lhe most advantageous pH for the reaction varies according to the temperature at which it is performed, but unsatisfactory results are obtainedwith aciditymuchgreaterthanpH 1 or les than pH 3. Inordertoattainthebestyields,a temperatm'e between 60 and C. must be maintained, andthercacfionisbestperformedinsamratedaqueons solution or in mixtures of water and an aliphatic alcohol as solvent. The same result can be obtained by melting the two compounds together. Advantageously hydran'ne salts containing two mineral acid equivalents are used but satisfactory results can also be obtained by using bydrazine salts containing one mineral acid equivalent or bymingmixturesofbothtypesofhydrazinesalts.

The analysisaswellasthechemicalandphysicalpropertiesofthenewhydrazine derivative indicateittohave a 'c structure (minusZH) correspondingto the formula and having two double bonds 'Ihereisagradedhydrogentalre-upofatleastonemol inthecatalytichydrogenationofthehydrazinederivative.

Thisnewhydrazine derivativehasamolecular formula C H ND, and a melting point of 233' C. In FIG. 1 of the accompanying drawings, the infra-red spectrum otthehydrazinederivativewhenitissuspendedinthe form of a Nujol mull is given. FIG. 2 shows the infia-redspectrmnofanapproximatelym396 solution of the hydran'ne derivative in CH;CI,. thicknes oflayer 1mm. InFIG. 1 andFlG.2thetr-ansmittance(vertical) isplottedagainstthewavelengthinmicronsmzontal). In FIG. 2, characteristic absorption bands are noted at 2.93 miu'ons, 5.97 microns and 6.22 miuons.

In FIG. 3 of the accompanying drawings the ultravioletspectmmofasolutionof.449mg.oftlnhydrazine derivativein SOmLofmethanolisgivemthicknesof layerlcm. 'I'hepercenthansmissionfiertimbisplotted against the wave-length (horizontal). A maximum is noted at 219 millimicrons, log e424.

Under energetic hydrogenation conditions three times themolaramotmtofhydrogenisnecessaryfortheforma o-e-mprolactam. The hydrogenation can i. in or \Y tion of a-amin be performed with hydrogen activated with nickel or palladium catalysts in a solvent such as water, dilute mineral acid (particularly with palladium charcoal as EXAMPLEI (a) Production of 2-Merhoxy-6-Aminohexene(2)- Acid Lactam 18.2 g. (0.1 mol) of 1!,1-dl0l1l0t0-e-C3Pl0lflt2i8lll, 16.2 g. (0.3 mol) of sodium methylate and 70 ml. of anhydrous methyl alcohol are boiled for 1 hour on a steam bath. After being initiated, the reaction is exothermic so that there is no need to apply heat for some time. Heat must finally be applied again towards the end to complete the reaction. After cooling, the reaction mixture is neutralised with 0.1 mol of glacial acetic acid, the sodium chloride is filtered olf, the methanol is evaporated off and the residue is disolved in 35 ml. of water. The aqueous solution is extracted twice with 20 ml. of chloroform each time and then three times with 10 ml. of chloroform each time. The combined chloroform solutions are dried, concentrated and the residue is fractionally distilled, whereupon the compotmd named above is obtained. It boils at 133-140 under 0.1 mm. pressure and melts at 96-98; yield 11 g.=80% of the theoretical.

(b) Production of Hydrau'ne Derivative 1.41 g. (10 millimol) of this 2-methoxy-6-aminohexene(2)-acid lactam or 1.55 g. of 2-ethoxy-6-aminohexene(2)-acid lactam which can be produced in a similar manner, 0.525 g. (5 millimol) of H,N.NH,.2HC1, 0.69 g. (5 millimol) of KH PO; and 20 ml. of water are heated for 1 hour on a steam bath (pH about 1). After cooling to excess H;N.NH;.2HC1 is filtered off under suction and the aqueous solution is then made phenolphthalein alkaline (pH 8.3). This is then extracted three times with 20 ml. of chloroform each time, the combined extracts are dried over Nat- 50. the solvent isevaporatedofiandtheresidueisrecrystallisedfmm methanol/ether. The hydrazine compound obtained melts at 232-234"; yield 50%.

Analysis:

H. N. Percent Percent Percent Cnlculated 57.56 7.25 29.40 l-orm 57.50 7. 9 2112 (e) Production of DL-a-dmino-e-caprolactam 250 mg. of the hydrazine derivative obtained by reacting Z-methoxyor 2-ethoxy-6-aminohexene(2)-acid lactam and hydran'ne (MI. 233', formula c u mo are dissolved in 25 ml. of water. 2.0 ml. of l N-hydrochloric acid are added to this solution. The solution is shaken withhydrogen in the presence of 50 mg. of palladium charcoal at room temperature and normal Undertheseconditionsoftheamountof hydrogen necessary for the hydrogenation of two double bonds and splitting of the hydrazo group, 80% is taken upwithin llhoursand 100% istakennpwithinZO'b horns. After the take-up of the theoretical amount of hydrogen, the catalyst is removed from the solution, the solution is concentrated and the residue is suspended in 5 ml. of ethanol and filtered. The filter residue is DL-eamino-e-caprolactam hydrochloride. It is in the form of white crystals which melt at 296-297"; yield 0.24 g. l(74%). The hydrogenation can be performed as folows:

260 mg. of the hydrazine derivative obtained by the reaction of Z-methoxyor 2-ethoxy-6aminohexene(2)- acid lactam and hydrazine are dissolved in l ml. of water. 0.1 ml. of l N-caustic soda lye are added to this solution and it is shaken with hydrogen in the presenoe of 5 g. of Raney nickel for 2 hours at 80 and atm. The catalyst is then filtered off and the residue is washed with alcohol. The solution is evaporated to dryness, the residue is taken up in a little alcohol and glacial acetic acid is added. The crystals are filtered oli under suction and washed with alcohol/ether (1:1). mg. of a-amino-caprolactam acetate which melts at -172 are obtained.

EXAMPLE 2 (a) Production of 2-Ethoay-6-Aminohexene(2)-Acid Lactam 9.1 g. of mm-dichlorH-caprolactam are added to a solution of 3.45 g. of sodium in 50 ml. of ethyl alcohol and the resulting solution is refluxed for 1 hour. The solution is then neutralised with 8.3 ml. of 6 N-hydrochloric acid, filtered and evaporated to dryness under reduced pressure. The residue is dissolved in a minimal amount of water, the aqueous solution is extracted with chloroform. the chloroform solution is concentrated and the oil which remains is distilled. According to analysis, the pale yellow oil which passes over at 112- ll3 under 0.04 mm. pressure, is 2-ethoxy-6-aminohexcne(2)-acid lactam (calculated C: 61.70; H: 8.17; N: 9.23; found C: 61.91; H: 8.44; N: 9.03)- On standing, colourles crystals in the form of needles slowly separate from the yellow oil. If the oil is rubbed with 2-5 parts by volume of ether in order to begin the crystallisation, then a good yield of 2.24 g. (29%) of the crystallised Z-ethoxy compound is obtained; M.P. 67-69.

(1;) Production of the Hydrazine Derivative and Hydrogenation 2.1 g. (20 millimol) of H=N.NH;.2HC1 are dissolved in 5 ml. of 70 warm water. The pH of the solution is adjusted to l with about 4.48 ml. of 4 N NaOl-L Then 6.2 g. (40 millimol) of 2-ethoxy-6aminohexene(2)-add lactarn or 5.64 g. of the 2-methoxy-5-arninohexene(2)- acid lactam obtained according to Example 1 (a) are added to the solution and the whole is reacted at 70 for about 75 minutes. During the reaction, the hydrochloric acid liberated is constantly neutralised or the acidity of the reaction mixture is kept constant at pH 1.

On completion of the reaction the hydran'ne derivative, without previously isolating it but after the addition of 30 of 2 N-hydrochloric acid and 500 mg. of palladium charcoal (5%), is hydrogenated for 24 hours at room temperature and normal pressure- The DL-aamino-e-caprolactam is worked up as described under (1) or (2) below:

(1) The aqueous solution is concentrated in vacuo, the residue is suspended in anhydrous ethanol, the pH of the suspension is adjusted to 9 with sodium ethylate, filtered and the filtrate is concentrated. Vacuum sublimationof the residue at 166-170 and 13 mm. Hg gives 2.95 g. of a-amino-e-caproladam which melts at 68-70; yield 58%.

(2) Ammonium reineckate dissolved in dimethyl formamide/water (1:1) is added to the aqueous solution. The aminocaprolactam-reineckate is filtered oil, dissolved in acetone/water (80:20) and excess aqueous silver sulphate solution is added. Excess silver sulphate and sulphuric acid are precipitated with the calculated amount of barium chloride, the barium sulphate is filtered off and the solution is concentrated. The crude a-aminocaprolactam hydrochloride which remains is taken up in alcohol, the solution is filtered and the filtrate is concentrated. 4.75 g. (72%) of hydrochloride which melts at 294 are obtained.

What we claim is:

1. Process for the production of u-amino-e-caprolactam and its salts which comprises heating a mixture of medichloro-e-caprolactam with 2 to 5 times the molar amount of a member selected from the group consisting of alkali metal methylate and alkali metal ethylate, to form a 2-substituted 6-aminohexene(2)-acid lactarn of the formula lire-zen wherein R represents a member selected from the group consisting of methyl and ethyl, mixing said lactam with approximately a half molar amount of a mineral acid salt of hydrazine at a pH between 0.8 and 3.0 and at a temperature of 60-120' C. to form a biheterocyclic hydran'ne derivative and then catalytically hydrogenating said hydrazine derivative.

2. Process according to claim 1 wherein the alcoholate is sodium methylate.

3. Process according to claim 2 wherein the alcoholate is employed in a methanol solution.

4. Process according to claim 1 wherein the alcoholate is sodium eflrylate.

5. A compound of the formula e cg t :-on

e 2 Hie-NH wherein R represents a member selected from the group comisting of methyl and ethyL 6. The compound, 2-methoxy-6-aminohexene(2)-acid lactam of the formula Bic-NH 7. The compound, 2-ethoxy-6-aminohexene(2)-add laetarn of the formula e c c-octm 0 A WI- e organic having the forum. 11 u u t s havin two double bonds, and also rm. emheadof two m the mm cyclic nuclei. said being dramcterized by the following properties: molecular formula C l-[@4 05 melting point 233' C.; solubility in methanol, methanol/ ether, chloroform and methylene chloride; absorption bands in the infra-red region of the spectrum, when in mineral oil, as shown in the following figure mu-In in maximum N 8 b S C I I 9 I I I 5 wherein percent transmittance (vertical) is plotted against wavelength in microns (horizontal); absorption bands in the infra-red region of the spectrum, when in a solution of methylene chloride, as shown in the following figure muse-earner! M r. r I t amount-nu. I It i 3 L 1 I I I U I l wherein percent transmitttance (vertical) is plotted against wavelength in microns (horizontal); a maximum in the ultra-violet spectrum at 219 log ==4.24, when in the solution in methanol, as shown in the following figure wherein percent transmittance (vertical) is plotted against wavelength in millimictons.

No references cited. 

1. PROCESS FOR THE PRODUCTIN OF A-AMINO-E-CAPROLACTAM AND ITS SALTS WHICH COMPRISES HEATING A MIXTURE OF A,ADICHLORO-E-CAPROLACTAM WITH 2 TO 5 TIMES THE MOLAR AMOUNT OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ALKALI METAL METHYLATE AND ALKALI METAL ETHYLATE, TO FORM A 2-SUBSTITUTED 3-AMINOHEXENE(2)-ACID LACTAM OF THE FORMULA
 5. A COMPOUND OF THE FORMULA 